Estrogenic compounds and animal growth promoters



Patented Mar. 12, 1968 United States Patent i e 3,373,027

acetic acid solution with hydrobromic acid. Aluminum ESTROGENIC cfig ggiigs AND ANIMAL chloride is another effective dealkylating agent. BenzylGROWTH PROMO ERS groups are also suitable masking groups and can beremoved by catalytic reduction. Benzyl ethers of F.E.S. ggg g' figi iggzg g fi g ggi gfig g g ggg 5 are described in copending applicationSerial No. 532,113,

Solvents Corporation, a corporation of Itlaryland filed Mar. 7, 1966,now abandoned and application Ser.

No Drawing. Continuation-impart of application Ser. No. 620359, filed1957- 561,371, June 29, 1966. This application Mar. 3, 1967, Thecompounds can be administered to ammals by Ser.No.62tl,261 any suitablemethod including oral and parenteral ad- 19 Claimsministrations. Forexample, the compound can be blended with ordinary feed containingnutritional values in an amount sufficient to produce the desired rateof growth ABSTRACT F THE DISCLGSURE and can thus be fed directly to theanimals, or the com- 0 OH pound can be suspended in a suitable injectionsuspen- R O a ll l slon medium such as peanut oil and in ectedparenterally. /C H( 2)s The amount of compound fed to an animal, ofcourse,

/ varies depending upon the animal, desired rate of growth and the like.CHZRI When the new compounds are to be administered in A% (CH2)5 feeds,an animal feed composition may be prepared conwhere R is selected fromthe group consisting of hydrotaining the usual nutritionally-balancedquantities of cargen, benzyl and lower alkyl, R is selected from thegroup bohydrates, proteins, vitamins and minerals, together consistingof nitroand amino-radicals and A is a rttdiwith the compound of thepresent invention. Some of cal selected from the group consisting of-CH=CH these usual dietary elements are grains, such as ground and -CHCH and animal feeds containing growth grain and grain by-products;animal protein substances, promoting amounts thereof. such as thosefound in fish meal and meat scraps, vegetable proteins like soybean oilmeal or peanut oil meal; vitaminaceous materials, e.g., vitamin A and Dmixtures;

This application is a continuation-in-part of applicariboflavinsupplements and other vitamin B complex memtion Serial filed J 111161966, W abfln- 30 bers; and bone meal and limestone to provide minerals.doned. A type of conventional feed material for use with cattle Thepresent invention relates to new compounds and includes alfalfa hay andground corn cobs together with an object of the present invention is toprovide comsupplementary vitaminaceous substances if desired. poundswhich exhibit estrogenic activity or aid in increas- The followingexamples serve to illustrate the inveuing the rate of growth inmeat-producing animals, e.g., tion. cattle, lamb and swine. Example IThe compounds of this invention are illustrated by the formula:

ylether is conducted with one equivalent of sodium eth- A oxide inabsolute ethanol to produces a sodio derivative /(J-0-('3]5[ 0n, OHwhich is collected and stirred with dilute acetic acid to produce: R OCHgR 1130-0 0 on,

A o'0 oH- o1;n)3 where A is CH CH or -CI-I=CH; R is hydrogen,substituted or unsubstituted alkyl, e.g., lower alkyl l C\ such asmethyl, ethyl, hexyl, etc., or aralkyl, e.g., benzyl; a CHNO and R is anamino-or nitro-radical. OH=CH-(C 2)3 Compound 1 The compounds of thepresent invention can be produced from the compound:

0 CH Example ll 3 OH l & The nitro group of Compound 1 is reduced byshak- 5 ing an acetic acid solution of the compound with a cat- C=Oalytic amount of Raney nickel at 100 p.s.i. hydrogen and H0 about 35 C.to produce.

\CH:CH(CH2)3 0 CH3 hereinafter referred to as the fermentationestrogenic H30 g O-H (CH2)3 substance (F.E.S.) by condensation ofnitromethane and F.E.S. with one equivalent of sodium ethoxide inalcoholic solution and conversion of the resulting sodio de- HC Orivative to the desired compound. 3 CH GHzNHi It is desirable to protectthe hydroxyl groups against 2* l 3 Compound 2 undesirable side reactionsbefore reaction which can llie accom lished b converting the hydroxylgroups on t e benzen e ring of F.E.S. to ethers, e.g., methyl ethers, asExample taught in US. Patent 3,239,342 and subsequently remov- The nitrogroup of Compound 1 is also reduced by ing the masking group toregenerate the hydroxyl group. 7 slowly adding 1 gram sod1um borohydrideto i 50 ml.

The hydroxyl group can be regenerated from, for exmethanol contalmng 0.3gram of Compound 1 while coolample, a methyl ether by hydrolysis or byrefluxing in mg the mixture. After heatlng for two hours on a steamCondensation of nitromethane with F,E.S. 2,4-dimethbath to evaporatemethanol, the residue is neutralized with HCl and extracted with etherto obtain:

Compound 3 Example IV Compound 1 is demethylated by heating at 120 C. inbenzene solution with two equivalents of aluminum chloride to produce:

Compound 4 Example V Dihydro F.E.S. 2,4-diethylether and F.E.S.2,4-dibenzylether are condensed according to the procedure of Example Ito produce the corresponding nitro derivatives.

Example VI Condensation of nitromethane with F.E.S. 2,4-dibenzylether isconducted with one equivalent of sodium ethoxide in absolute ethanol toproduce a sodio derivative which is collected and stirred with diluteacetic acid to produce:

CaH5CH2O Example VII The nitro group of the compound produced in ExampleVI is reduced by shaking an acetic acid solution of the compound with acatalytic amount of Raney nickel at 100 p.s.i. hydrogen and about 35 C.to produce:

Example VIII CsH5CHzO The nitro group of the compound produced inExample VI is also reduced by slowly adding 1 gram sodium borohydride to50 ml. methanol containing 0.3 gram of Compound 1 while cooling themixture. After heating for two hours on a steam bath to evaporatemethanol, the residue is neutralized with HCl and extracted with etherto obtain:

CHzNH:

CH CK-(C Hm OaH CHgO Example IX The compound produced in Example V1 isdebenzylated by catalytic reduction using Raney nickel catalyst andhydrogen at 100 p.s.i.g. and 35 C. to produce:

\CH2NH2 Compound 5 Example X Dihydro F.E.S. 2,4-diethylether and F.E.S.2,4-dimeth ylether are condensed according to the procedure of Example Ito produce the corresponding nitro derivatives.

Example XI Six head of cattle are fed a daily ration including a mixtureof alfalfa hay and ground corn cobs containing from S to 20 ounces per100 pounds feed of Compound 1 and their rate of growth is improved.

Example XII Six head of cattle are fed a daily ration including amixture of alfalfa hay and ground corn cobs containing from 5 to 20ounces per 100 pounds feed of Compound H 5 and their rate of growth isimproved.

The following are specific examples of animal feed compositions of thisinvention useful for increasing the rate of growth and feed efficiencyof young animals to market weight.

Example XIII For young beef cattle, i.e., calves to yearlings running totwo-year olds, each animal is given 5 to 20 milligrams per day of thecompound produced in Example I intimately admixed in about 18 to 22pounds per head per day of a complete pelleted ration for about 180days. The complete pelleted ration includes in addition to the compoundof Example I the following:

for the barley.

The compound of Example I is admixed with the above ingredients in astationary blender or a feed mix truck in the following amounts in gramsper ton to provide an appropriate complete pelleted feed with dosagelevels ranging from 5 to milligrams per head per day.

Grams/ton: Mg./head/day These gram amounts are premixed with, forexample, 10 pounds of soybean hulls prior to admixture with the otheringredients.

Example XIV For young swine, i.e., six week old pigs to about poundpigs, each animal is given 5 to 20 milligrams per day of the compound ofExample 11 intimately admixed in about 1 /2 to 5 /2 pounds per head perday of a grower ration until it reaches a weight of about 100 pounds.When the swine weigh between 90 and pounds the feed is changed to onewhereby each animal is given 20 to 50 milligrams per day of the compoundof Example II intimately admixed in about /2 to pounds per head per dayof a finisher ration until it reaches market weight of about 220 pounds.The grower and finisher ration include in addition to the compound ofExample II the following:

Grower, Finisher, percent percent Ground Yellow Corn Soybean Meal (44%protein) 1. Meat and Bone Scraps (50% rotein)- Dehydrate Alfalfa Meal(17%? Steamed Bone M Ground Limestone. Iodized Salt i. Vitamin,Antibiotic and Trace Mineral Premix- The compound of Example II isadmixed with the above ingredients in a blender in the following amountsin milligrams per pound to provide an appropriate feed with dosagelevels ranging from 6 to 96 milligrams per head per day.

Mg./pound: Mg./head/day Example XV For 4- to 10-month old lambs weighing50 to 70 pounds, each animal is given 1 to milligrams per day of onecompound of Example IV, intimately admixed in about 3 to 6 pounds perhead per day of a complete ration for to 90 days. The complete rationincludes in addition to the compound of Example IV the following:

The compound of Example IV is admixed with the above ingredients in ablender in the following amounts in milligrams per pound to provide anappropriate complete feed with dosage levels ranging from 1 to 15milligrams per head per day.

Mg./ pound: Mg./head/ day .5 2 1.0 4 1.5 6 2.0 8 2.5 10 3.75 15 ExampleXVI For broilers, i.e., day old to four-week-old chicks, a grower feedis prepared for feeding to the chicks for the first four weeks and afinisher feed is prepared for feeding the four week old chicks for thelast five weeks until they reach market weight of two and a half tothree pounds dressed. For each pound of weight gain, the chicks eatabout 1.5 to 2 pounds of feed. Thus they eat about 1.5 pounds of feedduring the first four weeks and about five pounds of feed during thenext five weeks. During the course of this feeding schedule, each birdshould receive a total of about 12 to 36 milligrams of the compound ofExample IX in the grower and finisher feed each of which includes inaddition to the compound of Example IX the following:

Grower Finisher (lbs.) Obs.) Ground Yellow Corn 1, 000 1, 200 SoybeanMeal (44% Protein) 700 500 Fish Meal (60% Protein).. 100 Alfalfa Meal 5050 0 30 80 80 35 40 10 10 15 l /(il-OCH(OH2)3 0H CHZR where R isselected from the group consisting of hydro- 2. The compound of claim 1wherein R is hydrogen, R is nitro and A is CH=CH.

3. The compound of claim 1 wherein R is hydrogen, R is nitro and A is-CH CH 4. The compound of claim 1 wherein R is hydrogen, R is amino andA is CH=CH.

5. The compound of claim 1 wherein. R is hydrogen, R is amino and A is-CH CH 6. The compound of claim 1 wherein R is lower alkyl, R is nitroand A is -CH=CH-.

7. The compound of claim 1 wherein R is lower alkyl, R is amino and A is-CH CH 8. The compound of claim 1 wherein R is lower alkyl, R is aminoand A is CH=CH-.

9. The compound of claim 1 wherein R is lower alkyl, R is amino and A isCH CH 10. An animal feed composition comprising a nutrient ration and agrowth promoting amount of the compound of claim 1.

No references cited.

A. LOUIS MONACELL, Primary Examiner. H. H. KLARE III, AssistantExaminer.

